Manage your subscription

Popping a pill could fix gene defect

By Sylvia Pagán Westphal

Simply popping a pill might be enough to overcome the type of genetic defect responsible for many cases of cystic fibrosis, muscular dystrophy and haemophilia. An experimental drug called PTC124 produces a working protein even though the gene remains defective.

Unlike gene therapy, it would work only for people with a particular kind of mutation. But while gene therapists are still struggling to develop safe and effective ways of correcting genetic faults, treatments like this could be available much sooner.

As many as a third of genetic diseases are caused by a premature stop mutation – a mutation in the middle of a gene’s sequence that stops the protein-making machinery at that spot. PTC124 binds to a key component of this machinery, allowing it to read past the misplaced stop signal. As a result, the full protein is made. Normal genes should not be affected, because their stop codon is at the end of the messenger RNA strand rather in the middle.

In 1996 scientists showed for the first time that an old antibiotic called gentamicin suppressed these misplaced stop signals in human DNA. Last week, the results of the first randomised, placebo-controlled trial were published in The New England Journal of Medicine (vol 349, p 1433), showing that when gentamicin is applied to the nostrils of people with cystic fibrosis, normal CFTR protein production is restored.

Advertisement

“What’s remarkable about this study is that someone has actually shown in that little patch of the nose that they can correct the abnormality,” says Peter Durie of the Hospital for Sick Children in Toronto, Canada. A larger trial where patients are inhaling the drug is already under way.

Poor absorbtion

Gentamicin may work for other genetic diseases too. In 2002, a small trial in Italy showed the antibiotic can restore production of the dystrophin protein in some cases of muscular dystrophy. None of the patients could normally make any dystrophin protein at all.

However, gentamicin has drawbacks. The body absorbs it poorly, so it must be injected or inhaled. And inhaling is fine for cystic fibrosis, but of little use for conditions such as muscular dystrophy. The antibiotic can also cause rare but serious side effects such as hearing loss and kidney damage.

That is where PTC124 comes in&colon; it was designed from the start to have similar properties to gentamicin but to be safer and more easily absorbed. “We are really in a different situation now, where we are trying to identify drugs based on how they should act,” says Langdon Miller, chief medical officer of PTC Therapeutics in New Jersey.

The drug was screened out of a pool of 175,000 synthetic molecules. Pre-clinical tests so far indicate that it is more potent than gentamicin and seems to have very low toxicity. “This could have very far-reaching effects,” claims David Bedwell, a microbiologist at the University of Alabama in Birmingham, who has tested the compound in his lab and is collaborating with the company.

In mice with muscular dystrophy the drug restores expression of the dystrophin protein found on the surface of muscle cells. Tests suggest the muscles regain some of their normal characteristics. Tests on mice with cystic fibrosis also suggest PTC124 restores production of functional CFTR.

All the results remain unpublished, though researchers working with the company say they hope to publish as soon as intellectual property issues are resolved. Miller says the company hopes to start clinical trials with healthy volunteers as early as next 2004.

But a premature stop mutation will not always be the cause of a particular genetic disease. So even if PTC124 or gentamicin make it to the market for treating genetic diseases, they will not be a magical cure for everyone.